RNA m6A methylation-mediated progesterone production in cumulus cells affects postovulatory oocyte aging

ABSTRACT: Mammalian postovulatory oocyte aging (POA) rapidly deteriorates oocyte quality and developmental potential, limiting female reproductive efficiency and the outcome of assisted reproductive technology. Although it is known that metabolic coordination within the cumulus–oocyte complex is essential for viability, metabolic disorders and progesterone deficiency in cumulus cells are key hallmarks of ovarian dysfunction and oocyte quality decline. However, the precise molecular pathways coupling epitranscriptomic modifications to progesterone and metabolic communication during POA remain poorly defined. In this study, we showed that a decline in METTL3-mediated m6A methylation in cumulus cells drives metabolic decay by disrupting a progesterone-dependent mitochondrial pyruvate transport pathway during POA. Inhibition of this METTL3/IGF2BP2–m6A–LZTS1 axis leads to progesterone deficiency in cumulus cells, which subsequently downregulates mitochondrial pyruvate carrier 2 (MPC2). This reduction in MPC2 prevents pyruvate transport into the mitochondria, causing cellular pyruvate accumulation, ATP depletion, and senescence in POA oocytes. Crucially, in vivo progesterone replenishment via fallopian tube infiltration restores MPC2 expression, mitochondrial dysfunction, and improves subsequent blastocyst development of POA oocytes. These findings reveal an epitranscriptomic–hormonal regulatory axis that mediates mitochondrial energy homeostasis within the cumulus–oocyte complex during POA, and provide potential therapeutic targets to preserve oocyte quality and improve assisted reproductive outcomes.

ORGANISM(S): Sus scrofa

PROVIDER: GSE353373 | GEO | 2026/11/09

REPOSITORIES: GEO